A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells

Abstract

Both purinergic signaling through nucleotides such as ATP (adenosine 5′-triphosphate) and noradrenergic signaling through molecules such as norepinephrine regulate vascular tone and blood pressure. Pannexin1 (Panx1), which forms large-pore, ATP-releasing channels, is present in vascular smooth muscle cells in peripheral blood vessels and participates in noradrenergic responses. Using pharmacological approaches and mice conditionally lacking Panx1 in smooth muscle cells, we found that Panx1 contributed to vaso-constriction mediated by the α1 adrenoreceptor (α1AR), whereas vasoconstriction in response to serotonin or endothelin-1 was independent of Panx1. Analysis of the Panx1-deficient mice showed that Panx1 contributed to blood pressure regulation especially during the night cycle when sympathetic nervous activity is highest. Using mimetic peptides and site-directed mutagenesis, we identified a specific amino acid sequence in the Panx1 intracellular loop that is essential for activation by α1AR signaling. Collectively, these data describe a specific link between noradrenergic and purinergic signaling in blood pressure homeostasis.

A Germline Variant in the PANX1 Gene Has Reduced Channel Function and Is Associated with Multisystem Dysfunction

“…For these experiments, we made use of 293T cells, devoid of endogenously expressed CBX-sensitive currents (45,46), and we assessed pannexin function by recording membrane currents generated by voltage ramps from Ϫ100 to ϩ100 mV. In 293T cells expressing R217H, ramp currents recorded at ϩ100 mV were reduced by ϳ50% compared with wild-type PANX1 (Fig.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…In addition to their role in nucleotide release from apoptotic cells, the pannexin channels are also involved in regulating the integrity of the dying cells, 63 regulation of vascular constriction via nucleotides released by non-apoptotic mechanisms, 64 and cancer cell migration. 65 Owing to the ubiquitous expression 66 and vast regulatory mechanisms of Panx1 activation, 61,67 novel cell-type-specific knock-out and transgenic mice affecting apoptosis-specific activation may be necessary to understand its involvement during cell clearance in vivo.…”

At the cross-point of connexins, calcium, and ATP: blocking hemichannels inhibits vasoconstriction of rat small mesenteric arteries

“…[17][18][19] Pannexins are related to the Cx-protein family: they have a similar topology but no sequence homology with Cxs and form plasma membrane channels that, like Cx-hemichannels, are Ca 2þ -permeable and function as ATP release channels. 20,21 Panx1 is expressed in SMCs of resistance arteries in several vascular beds 22 and plays a role in the vasoconstriction induced by a1-adrenergic stimulation of thoracodorsal arteries. 23, 24 Here we aimed to investigate whether Cx-hemichannels are involved in SMC Ca 2þ oscillations and control of vascular tone.…”